1. Field of the Invention
This invention relates to a fluorescence detecting apparatus suitable for use in a fluorescence diagnosing system; wherein a diagnosis of a tumor is carried out by irradiating excitation light to a region of interest in a living body, to which a photosensitive substance, that has a strong affinity for the tumor and is capable of producing fluorescence when it is excited with the excitation light, has been administered, and by detecting the intensity of fluorescence, which is produced by the photosensitive substance and an intrinsic dye in the living body when the region of interest in the living body is exposed to the excitation light; or wherein a diagnosis of a tumor is carried out by irradiating excitation light to a region of interest in a living body, to which no photosensitive substance has been administered, and by detecting the intensity of intrinsic fluorescence, which is produced by an intrinsic dye in the living body when the region of interest in the living body is exposed to the excitation light.
2. Description of the Related Art
Extensive research has heretofore been conducted on the so-called photodynamic diagnosis (PDD) technique. With the PDD technique, a photosensitive substance (such as ATX-S10, 5-ALA, NPe6, HAT-DO1 or Photofrin-2), which has an affinity for a tumor and is capable of producing fluorescence when it is excited with light, is employed as a fluorescent diagnosis drug. The photosensitive substance is administered to a living body and is absorbed by a tumor part, such as a cancer, of the living body. Excitation light, which has wavelengths falling within the excitation wavelength range for the photosensitive substance, is then irradiated to the region containing the tumor part, and fluorescence is thereby produced from the fluorescent diagnosis drug having been accumulated at the tumor part. By the detection of the fluorescence, the location and infiltration range of the diseased part is displayed as an image, and the displayed image is used in conducting a diagnosis of the tumor part.
Fluorescence diagnosing systems for carrying out the PDD technique have been disclosed in, for example, U.S. Pat. No. 4,556,057, and Japanese Unexamined Patent Publication Nos. 1(1989)-136630 and 7(1995)-59783. Basically, each of the disclosed fluorescence diagnosing systems comprises: an excitation light irradiating means for irradiating excitation light, which has wavelengths falling within the excitation wavelength range for a photosensitive substance, to a living body; an imaging means for detecting the fluorescence produced by the photosensitive substance and forming a fluorescence image of the living body, and an image displaying means for receiving the output from the imaging means and displaying the fluorescence image. In many cases, the fluorescence diagnosing systems take on the forms built in endoscopes to be inserted into the body cavities, operating microscopes, or the like.
Techniques for making a diagnosis of a tumor part without a photosensitive substance being administered to the living body have also been proposed. With the proposed techniques, excitation light, which has wavelengths falling within the excitation wavelength range for an intrinsic dye in the living body, is irradiated to a region of interest in the living body (i.e., the region which is to be used in making a diagnosis). The intrinsic dye in the living body is thus excited by the excitation light and produces fluorescence. By the detection of the fluorescence, the location and infiltration range of the diseased part is displayed as an image, and the displayed image is used in conducting a diagnosis of the tumor part.
Further, a different fluorescence diagnosing system has been proposed in, for example, Japanese Patent Application No. 7(1995)-252295. With the proposed fluorescence diagnosing system, instead of obtaining the two-dimensional image as described above, the intensity of fluorescence produced from each specific point in a region of a living body is detected. A judgment is then made as to whether each point in the region of the living body belongs or does not belong to a tumor part.
However, the above fluorescence diagnosing systems have the problems described below. Specifically, since a region in a living body has protrusions and recesses, the distance between the light source of the excitation light irradiating means and the region of interest in the living body is not uniform. Therefore, the irradiance of the excitation light at each part of the living body, which is exposed to the excitation light, is usually non-uniform. In general, the intensity of fluorescence is approximately in proportion to the irradiance of the excitation light, and the irradiance of the excitation light at a part of the living body exposed to the excitation light is in inverse proportion to the square of the distance between the light source of the excitation light irradiating means and that part of the living body exposed to the excitation light. Accordingly, the problems occur in that a normal part, which is located close to the light source, may produce the fluorescence having a higher intensity than the intensity of the fluorescence produced by a diseased part, which is located remote from the light source. The problems also occur in that the intensity of the fluorescence from a diseased part, which is located at a position inclined with respect to the incident direction of the excitation light, may become markedly low. Thus, if the irradiance of the excitation light is non-uniform, the intensity of the fluorescence will vary in accordance with the level of the irradiance of the excitation light, and therefore an error will often be made in diagnosis of a tumor part.
Therefore, fluorescence diagnosing systems, which are designed such that a change in the intensity of fluorescence due to the non-uniformity of the distance with respect to the region of interest in the living body may be compensated for, have been proposed in, for example, U.S. Pat. No. 4,768,513 and Japanese Patent Publication No.3 (1991)-58729. With the fluorescence diagnosing system proposed in Japanese Patent Publication No. 3(1991)-58729, excitation light is irradiated to a region of a living body, to which a photosensitive substance having a strong affinity for a diseased part has been administered, and the fluorescence produced by the photosensitive substance is detected. Also, the excitation light reflected from that region of the living body is detected. An image operation is then carried out including a division operation between the fluorescence component and the reflected excitation light component by each other. By the division operation, the term due to the distance with respect to the region of interest in the living body is cancelled. However, in the results of the division operation between the fluorescence component and the reflected excitation light component by each other, the term concerning the reflectivity of the portion exposed to the excitation light remains uncancelled. Consequently, the problems remain uneliminated in that a fluorescence image accurately reflecting the distribution of the fluorescent diagnosis drug cannot be obtained.
A different fluorescence imaging technique is proposed in, for example, xe2x80x9cFluorescence Imaging of Early Lung Cancer,xe2x80x9d Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Vol. 12, No. 3, 1990. With the proposed technique, intrinsic fluorescence, which is produced by an intrinsic dye in an region of interest in a living body when the region of interest is exposed to excitation light, is separated into a fluorescence component corresponding to a green wavelength range (hereinbelow referred to as the xe2x80x9cgreen wavelength component Gxe2x80x9d) and a fluorescence component corresponding to a red wavelength range (hereinbelow referred to as the xe2x80x9cred wavelength component Rxe2x80x9d). An image operation is then carried out including a division operation between the red wavelength component R and the green wavelength component G by each other, and the result of the division operation is displayed. The proposed technique utilizes the findings in that the spectrum of the intrinsic fluorescence produced by a normal part is different from the spectrum of the intrinsic fluorescence produced by a diseased part. Particularly, when the spectrum of the intrinsic fluorescence, which is produced by the intrinsic dye at a normal part in the living body, and the spectrum of the intrinsic fluorescence, which is produced by the intrinsic dye at a diseased part in the living body, are compared with each other, the intensity of the green range of the spectrum obtained from the diseased part is markedly lower than the intensity of the green range of the spectrum obtained from the normal part. Therefore, the degree of reduction in the intensity of the green wavelength component G of the intrinsic fluorescence obtained from the diseased part, as compared with the intensity of the green wavelength component G of the intrinsic fluorescence obtained from the normal part, is markedly higher than the degree of reduction in the intensity of the red wavelength component R of the intrinsic fluorescence obtained from the diseased part, as compared with the intensity of the red wavelength component R of the intrinsic fluorescence obtained from the normal part. Therefore, only the intrinsic fluorescence from the diseased part can be specifically extracted by carrying out the division operation of R/G and can be displayed as a visual image. With the proposed technique, the term of the fluorescence intensity depending upon the distance between the excitation light source (i.e., the excitation light irradiating means) and the region of interest in the living body and the distance between the region of interest in the living body and the fluorescence receiving means can be canceled. However, the proposed technique has the problems in that the signal-to-noise ratio cannot be kept high, since the intensity of the intrinsic fluorescence from the diseased part is markedly low.
Accordingly, a different fluorescence diagnosing technique utilizing the red/green ratio has been proposed in xe2x80x9cFluorescence Image Diagnosis of Cancer Using Red/Green Ratioxe2x80x9d by Tokyo Medical College and Hamamatsu Photonics K.K., 16th symposium of The Japanese Society of Laser Medical Science, 1995.
With the proposed technique, the intensity of red fluorescence from a diseased part is amplified by using a fluorescent diagnosis drug, which is capable of accumulating at the diseased part and producing red fluorescence, and an operation of R/G is carried out. As a result, a fluorescence image can be obtained such that the intensity of fluorescence from the diseased part may be kept higher than that with the aforesaid technique proposed in xe2x80x9cFluorescence Imaging of Early Lung Cancer.xe2x80x9d
In cases where the operation of R/G is carried out as in the two techniques described above, the term of the fluorescence intensity depending upon the distance between the excitation light source and the region of interest in the living body and the distance between the region of interest in the living body and the fluorescence receiving means can be ignored.
However, the intensity of the green intrinsic fluorescence component from the diseased part is markedly low. Therefore, with the two techniques described above, the problems occur in that the division by the value of zero often occurs, and an error readily occurs in making the division operation.
In addition, there has been another problem with those fluorescence diagnosing systems as described above. In conducting the fluorescence diagnosis, multiple images of different wavelength ranges are required for identifying differences between spectral patterns of the normal tissues and diseased tissues. To obtain such multiple images, the fluorescence detecting apparatus in each of the fluorescence diagnosing systems as described above has required use of multiple imaging devices each provided with a color filter of a single color fixed on a detection surface thereof. Such a configuration with the multiple imaging devices undesirably increases the operation cost and the size of the fluorescence detecting apparatus.
One object of the present invention is to provide a fluorescence detecting apparatus, wherein the fluorescence intensity depending upon the distance between an excitation light source and a region of interest in a living body exposed to excitation light and upon the distance between the region of interest and a fluorescence receiving means is corrected such that no operation error may occur.
Another object of the present invention is to provide a fluorescence detecting apparatus, which enables operation processing realizing a high signal-to-noise ratio to be carried out.
A specific object of the present invention is to provide a fluorescence detecting apparatus, which enables the formation of a fluorescence image, that has good image quality and is capable of serving as an effective tool in the efficient and accurate diagnosis of an illness.
Still another object of the present invention is to provide a fluorescence detecting apparatus with a compact configuration requiring a relatively low operation cost.
The present invention provides a first fluorescence detecting apparatus, wherein excitation light is irradiated to a region of interest in a living body, to which a photosensitive substance (i.e., a fluorescent diagnosis drug) has been administered, and wherein fluorescence, which is produced from the region of interest in the living body when the region of interest is exposed to the excitation light, is detected. Specifically, the present invention provides a first fluorescence detecting apparatus, comprising:
i) an excitation light irradiating means for irradiating excitation light to a region of interest in a living body to which a fluorescent diagnosis drug, that is capable of producing fluorescence when excited with the excitation light has been administered, said excitation light covering wavelengths falling within an excitation wavelength range for said fluorescent diagnosis drug and an intrinsic dye in the living body, said intrinsic dye being capable of producing fluorescence when excited with the excitation light,
ii) a fluorescence detecting means for detecting first and second fluorescence components,
said first fluorescence component being either one of:
a) an entire fluorescence component covering wavelengths falling within a wavelength range which contains: a wavelength range of extrinsic fluorescence produced by said fluorescent diagnosis drug in said region of interest in the living body, and a wavelength range of intrinsic fluorescence produced by said intrinsic dye in said region of interest in the living body, and
b) a fluorescence sum component which is the sum of a fluorescence component covering wavelengths falling within a part of the wavelength range of the extrinsic fluorescence produced by said fluorescent diagnosis drug in said region of interest in the living body, and a fluorescence component covering wavelengths falling within a part of the wavelength range of the intrinsic fluorescence produced by said intrinsic dye in the living body, and
said second fluorescence component being either one of:
a) a fluorescence component covering wavelengths falling within a part of the wavelength range of the extrinsic fluorescence, and
b) a fluorescence difference component which is the difference between a fluorescence component covering wavelengths falling within a part of the wavelength range of the extrinsic fluorescence, and a fluorescence component covering wavelengths falling within a part of the wavelength range of the intrinsic fluorescence, and
iii) a division means for carrying out a division between the first fluorescence component and the second fluorescence component, wherein
the fluorescence detecting means comprises:
i) a color mosaic filter for separating the fluorescence emitted from the region of interest into the first fluorescence component and the second fluorescence component, and
ii) a detecting means for detecting the first and second fluorescence components in a two-dimensional manner, and wherein
the color mosaic filter is fixed on a fluorescence detecting surface of the detecting means.
In the first fluorescence detecting apparatus in accordance with the present invention, it is desirable to employ light covering wavelengths falling within a wavelength range in the vicinity of an excitation peak wavelength for the fluorescent diagnosis drug as the excitation light, such that the signal-to-noise ratio of the fluorescence component detected by each fluorescence detecting means may be enhanced. Alternatively, it is also desirable to employ as the excitation light the light covering wavelengths falling within a wavelength range in the vicinity of the excitation peak wavelength for the fluorescent diagnosis drug and light covering wavelengths falling within a wavelength range in the vicinity of an excitation peak wavelength for the intrinsic dye in the living body.
The term xe2x80x9cexcitation peak wavelength for a fluorescent diagnosis drugxe2x80x9d as used herein means the wavelength of the excitation light, which causes the fluorescent diagnosis drug to produce the extrinsic fluorescence having the highest possible intensity. Also, the term xe2x80x9cexcitation peak wavelength for an intrinsic dye in a living bodyxe2x80x9d as used herein means the wavelength of the excitation light, which causes the intrinsic dye in the living body to produce the intrinsic fluorescence having the highest possible intensity.
The present invention also provides a second fluorescence detecting apparatus, wherein excitation light is irradiated to a region of interest in a living body, to which no photosensitive substance (i.e., fluorescent diagnosis drug) has been administered, and wherein intrinsic fluorescence, which is produced by an intrinsic dye in the region of interest in the living body when the intrinsic dye is excited with the excitation light, is detected. Specifically, the present invention provides a second fluorescence detecting apparatus, comprising:
i) an excitation light irradiating means for irradiating excitation light to a region of interest in a living body, said excitation light covering wavelengths falling within an excitation wavelength range for an intrinsic dye in the living body, said intrinsic dye being capable of producing fluorescence when excited with the excitation light,
ii) a fluorescence detecting means for detecting first and second fluorescence components,
said first fluorescence component being either one of:
a) an entire intrinsic fluorescence component covering wavelengths falling within a visible wavelength range, which contains a comparatively short wavelength range and a comparatively long wavelength range among a wavelength range of intrinsic fluorescence produced by said intrinsic dye in said region of interest in the living body, and
b) a fluorescence sum component, which is the sum of a fluorescence component covering wavelengths falling within a part of the comparatively short wavelength range among the wavelength range of the intrinsic fluorescence produced by said intrinsic dye in said region of interest in the living body, and a fluorescence component covering wavelengths falling within a part of the comparatively long wavelength range among the wavelength range of the intrinsic fluorescence, and
said second fluorescence component being either one of:
a) a fluorescence component covering wavelengths falling within a part of the comparatively long wavelength range among the wavelength range of the intrinsic fluorescence, and
b) a fluorescence difference component which is the difference between: a fluorescence component covering wavelengths falling within a part of the comparatively short wavelength range among the wavelength range of the intrinsic fluorescence, and a fluorescence component covering wavelengths falling within a part of the comparatively long wavelength range among the wavelength range of the intrinsic fluorescence, and
iii) a division means for carrying out a division operation between the first fluorescence component and the second fluorescence component, wherein
the fluorescence detecting means comprises:
i) a color mosaic filter for separating the fluorescence emitted from the region of interest into the first fluorescence component and the second fluorescence component, and
ii) a detecting means for detecting the first and second fluorescence components in a two-dimensional manner, and wherein
the color mosaic filter is fixed on a fluorescence detecting surface of the detecting means.
In the second fluorescence detecting apparatus in accordance with the present invention, it is desirable to employ light covering wavelengths falling within a wavelength range in the vicinity of an excitation peak wavelength for the intrinsic dye in the living body as the excitation light, such that the signal-to-noise ratio of the fluorescence component detected by each fluorescence detecting means may be enhanced.
The present invention also provides a third fluorescence detecting apparatus comprising:
i) an excitation light irradiating means for irradiating excitation light to a region of interest in a living body,
ii) a fluorescence detecting means for detecting at least two fluorescence components of desired wavelength ranges extracted from fluorescence emitted from the region of interest irradiated with the excitation light, and
iii) a signal processing means for processing signals representing said at least two fluorescence components detected by the fluorescence detecting means in a predetermined manner, wherein
the fluorescence detecting means comprises:
i) a color mosaic filter for separating the fluorescence emitted from the region of interest into said at least two fluorescence components, and
ii) a detecting means for detecting said at least two fluorescence components in a two-dimensional manner, and wherein
the color mosaic filter is fixed on a fluorescence detecting surface of the detecting means.
The color mosaic filter used in the third fluorescence detecting apparatus may include filter elements of primary colors, or may include filter elements of complementary colors.
In the first and second fluorescence detecting apparatuses in accordance with the present invention, the fluorescence detecting means may detect the fluorescence produced from each of different points in the region of interest. Alternatively, the fluorescence detecting means may carry out two-dimensional detection of the fluorescence (i.e., the extrinsic fluorescence or the intrinsic fluorescence) produced from the region for interest and may thereby obtain a fluorescence image of the region of interest.
With the first and second fluorescence detecting apparatuses in accordance with the present invention, wherein the entire fluorescence component covering the wavelengths falling within the predetermined wavelength range or the fluorescence sum component, which is the sum of the fluorescence components each covering wavelengths falling within the desired wavelength range, is employed as the denominator in the division, the value of the denominator in the division can be kept sufficiently large. Therefore, the problem of an operation error due to division by the value of zero can be prevented. Also, the adverse effects from fluctuation in the intensity of fluorescence, due to the distance between the excitation light irradiating means and the region of interest in the living body and the distance between the region of interest in the living body and the fluorescence receiving means, can be eliminated reliably.
Further, in cases where light covering wavelengths falling within a wavelength range in the vicinity of the excitation peak wavelength for the fluorescent diagnosis drug and/or covering wavelengths falling within a wavelength range in the vicinity of the excitation peak wavelength for the intrinsic dye in the living body is employed as the excitation light, the values of both the denominator and the numerator in the division can be kept sufficiently large. Therefore, operation processing realizing a high signal-to-noise ratio can be carried out.
The first and second fluorescence detecting apparatuses in accordance with the present invention may be applied to a fluorescence diagnosing system, wherein a fluorescence image is formed using an imaging means, such as an image sensor, as the fluorescence detecting means. In such cases, a fluorescence image can be obtained, in which the adverse effects from fluctuation in the intensity of fluorescence due to the aforesaid distances have been eliminated. Also, a fluorescence image having good image quality with a high signal-to-noise ratio can be obtained. Therefore, a fluorescence image can be obtained, which has good image quality and is capable of serving as an effective tool in the efficient and accurate diagnosis of an illness.
In either of the first, second or third fluorescence detecting apparatus in accordance with the present invention, the color mosaic filter separates the fluorescence emitted from the region of interest into a plurality of fluorescence components of desired wavelength ranges. Accordingly, the configuration of the fluorescence detecting means can be simplified. In addition, at least two fluorescence components of desired wavelength ranges can be detected using a single detecting means, providing a fluorescence detecting apparatus with a compact configuration requiring a relatively low operation cost.
In the case where the color mosaic filter includes the filter elements of primary colors, each fluorescence component can be extracted and detected requiring only simple signal processing.
In the case where the color mosaic filter includes the filter elements of complementary colors, each fluorescence component of a desired wavelength range can be derived from the fluorescence components of wavelength ranges corresponding to the complementary colors, i.e., the fluorescence emitted by the region of interest is used with higher efficiency. Accordingly, the S/N ratio of each fluorescence component can be improved as effects of noises are restrained.